The Journal of biological chemistry
May 25, 2012
Simon Bulling, Klaus Schicker, Yuan-Wei Zhang et al.
124 citations
Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, unlike all other known inhibitors which compete with serotonin. It binds to a distinct site accessible from the cell exterior, not the substrate-binding site, and increases accessibility in the cytoplasmic permeation pathway. Ibogaine also noncompetitively inhibits the dopamine transporter (DAT) and blocks substrate-induced currents in both transporters. The inhibition is not reversed by increasing substrate concentration, and ibogaine does not form a long-lived complex with SERT but binds directly to the inward-open conformation. A kinetic model distinguishes ibogaine's noncompetitive action from cocaine's competitive action.
Addiction biology
March 1, 2014
Xaver Koenig, Michael Kovar, Stefan Boehm et al.
50 citations
Therapeutic concentrations of ibogaine, an alkaloid from the African shrub Tabernanthe iboga used in alternative medicine for its anti-addictive properties, reduce currents through human ether-a-go-go-related gene potassium channels. This provides a mechanism by which ibogaine may generate life-threatening cardiac arrhythmias, consistent with anecdotal evidence that it can disturb heart rhythm.
The Journal of pharmacology and experimental therapeutics
February 1, 2014
Patrick Thurner, Anna Stary-Weinzinger, Hend Gafar et al.
41 citations
Ibogaine, a psychoactive alkaloid used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. Experiments on mammalian kidney cells expressing hERG channels showed that block occurred from either side of the cell membrane and depended on pH. Block happened only when channels were activated, not when resting. Stronger depolarizations increased block speed and extent. The drug shifted channel activation and inactivation to more negative voltages, slowed deactivation, and accelerated inactivation. Mutations Y652A and F656A reduced ibogaine's potency, but an inactivation-deficient mutant remained sensitive. Molecular docking suggested binding inside the channel cavity regardless of ibogaine's protonation state. Kinetic modeling indicated preferential binding to open and inactivated states.
Cardiovascular toxicology
April 1, 2017
Lena Rubi, Daniel Eckert, Stefan Boehm et al.
18 citations
The anti-addiction drug ibogaine and its main metabolite noribogaine slow action potential repolarization in human heart cells, providing the first experimental proof that ibogaine poses a risk of cardiac arrhythmias for humans. Using whole-cell patch clamp recordings on human ventricular-like cardiomyocytes derived from induced pluripotent stem cells, therapeutic concentrations of both substances significantly retarded repolarization. This explains the delayed incidence of cardiac adverse events observed several days after ibogaine intake. The findings suggest that ibogaine may prolong the QT interval in the electrocardiogram, leading to life-threatening arrhythmias and sudden death.